Alzheimer's disease is an incurable neurodegenerative disorder, in which cells throughout the brain become damaged and die. Progression of Alzheimer's leads to memory loss, behavioral and emotional disturbances, diminished motor skills and personality changes. The biochemical hallmarks of Alzheimer's are the development of protein plaques composed of amyloid beta, and the development of neurofibrillary tangles that involve a protein called tau. Research into the causes of and pathology of Alzheimer's disease has identified a number of biochemical changes that occur within the cells and throughout the brain, which contribute to improper cell functioning and cell death.
Improper APP Processing
At the onset of Alzheimer's, a biochemical change occurs in cells that results in improper processing of a protein called amyloid precursor protein, or APP. APP is normally activated after being cleaved by a series of proteins, which care called proteases. In Alzheimer's disease, the proteases responsible for cleaving APP begin to malfunction, and start to generate a bi-product called amyloid beta.
Amyloid beta has a toxic effect on the cells. In a 2009 report in Nature Reviews, Dr. K. Whalley explains that once one amyloid beta molecule has been generated, it affects the proteases in the cell to promote the generation of more amyloid beta molecules. Eventually, the toxic amyloid beta forms plaques within the brain, which drive the development of Alzheimer's.
Disruption of Signalling
Once amyloid beta aggregates begin to form within the brain, the cells surrounding the toxic plaques begin to change their behavior in response to the amyloid beta. The language that the cell uses to transmit signals and regulate behavior is called signal transduction. Amyloid beta changes the signal transduction events within the cell to change cell behavior and contribute to the development of Alzheimer's.
One signal transduction mechanism that is affected by amyloid beta involves a protein called GSK-3. In normal cells, GSK-3 plays a role in preventing cell death, by sending pro-survival signals. In Alzheimer's disease, the function is GSK-3 is altered so that it no longer send pro-surval signals. Additionally, a 2006 report in the Journal of Neurochemistry indicates that GSK-3 begins to take on other functions within the cell, that contribute to the progression of Alzheimer's.
Breakdown of Cellular Structure
Changes within the signal transduction of GSK-3 lead to a breakdown of the structure of the cell, and ultimately lead to cell death. There are a number of structural proteins that support the structure of the cell, which make up the cytoskeleton. Among these is a protein called tau, which plays a role in maintaining the cytoskeleton. If tau becomes inactive, cytoskeleton is weakened, and the fibers can twist and tangle with each other, damaging the cell and forming structures called neurofibrillary tangles, or NFTs. The development of NFTs causes brain cell death.
In a 2010 report published in Expert Review of Neuropathics, Dr. J. Avila reported that GSK-3 in Alzheimer's disease promotes the formation of NFTs. It does so by chemically modifying tau and inactivating it, so that it cannot contribute to the cytoskeleton. Following inactivation of tau, the affected cells form NFTs and die.
Continuing the Cycle
After the formation of NFTs within a cell, and the proceeding cell death, any amyloid beta that accumulated within that diseased cell is released into the brain, where it can affect neighboring cells and lead to more cell death. Without medication to slow the progression of Alzheimer's the cycle will continue and lead to massive cell death within the brain.
References
- Nature Reviews: Neurodegenerative disease: Amyloid-β and PrPC: it takes two
- National Institutes of Health: Effects of endogenous beta-amyloid overproduction on tau phosphorylation in cell culture.
- National Institutes of Health: Role of glycogen synthase kinase-3 in Alzheimer's disease pathogenesis and glycogen synthase kinase-3 inhibitors.
